PRODRUGS OF CARBOXYLIC ACIDS
• Ester formation
is the most common prodrug design
strategy to increase lipophilicity by masking
carboxylic
acids, phosphates, and other charged groups.
• Such prodrug is activated by
enzymatic
(esterase) or
chemical hydrolysis
.
• Ester prodrugs are most often used to enhance
oral
absorption
and thus passive membrane permeability
of poorly permeable compounds.
• Enalapril is an
angiotensin converting enzyme (ACE) inhibitor
used in the treatment of
hypertension
and some types of
chronic
heart failure
.
• As a
prodrug
, enalapril is metabolised in vivo to the active form
enalaprilat and ethanol by various
esterases
.
• Enalaprilat has potent therapeutic activity when administered
intravenously, but its high polarity causes it to be poorly
absorbed from gastrointestinal tract.
• Esterification of enalaprilat to enalapril enhances the affinity
for the intestinal peptide carrier-mediated transport system,
increasing the intestinal absorption and resulting in improved
bioavability.
N H O N O O COOH N H O N HO O COOH Carboxylesterases Enalapril Enalaprilat CH3CH2OH + Ethanol• Oseltamivir
is an ethyl ester prodrug of
oseltamir
carboxylate,
requiring ester hydrolysis for conversion to
the active form.
• Oseltamivir is readily absorbed from gastrointestinal tract
after oral administration and converted by hepatic
esterases to oseltamir carboxylate with an absolute
bioavability of 80%.
• Oseltamir carboxylate is a potent carboxylic
transition-state analog inhibitor of influenza virus, neuraminidase,
with activity against both influenza A and B viruses.
CH3CH2OH + Ethanol NH2 O NH O O O NH2 O N H OH O O Carboxyesterases
• Ximelagatran was designed to increase the bioavability of melagatran, which was the first member of orally administered potent thrombin inhibitors.
• The double prodrug ximelagatran is composed of an ethyl ester group in place of the carboxylic acid and an N- hydroxyamidine group in the amidine end of melagatran.
• By adding these groups, the highly hydrophilic and charged melagatran is converted into a much more lipophilic molecule that is uncharged at physiological pH.
• Ximelagatran increased bioavability to 18-24% and also improved
pharmacokinetic properties relating to lower variability in bioavailability and lack
of food effects.
• The formation of melagatran from ximelagatran requires two metabolic reactions. The ester group is cleaved by esterases and N- hydroxyamidine group is reduced to an amidine group in the liver.
N NH O O O O NH NH2 OH N N NH OH O O O NH NH2 NH Hydrolysis N-reduction Ximelagatran Melagatran + H2O + CH3CH2OH Ethanol
